The sympathoadrenal hormones epinephrine and norepinephrine, released under conditions of physical or emotional stress, have two effects on the heart. Acutely, they increase myocardial inotropy, chronotropy, and lusitropy by activating cardiac beta-adrenergic receptors (beta-AR). Chronically, they stimulate myocardial hypertrophy through activation of cardiac alpha-adrenergic receptors. These distinct cardiac catecholamine responses are inextricably linked in that cardiac hypertrophy appears to be invariably associated with dysfunction of beta-AR signaling. We propose to test the hypothesis that PKCalpha activation leads to cardiac adrenergic unresponsiveness by uncoupling beta-AR from their signaling effectors in myocardial hypertrophy. Our proposed approach will examine beta-AR receptors and their downstream effectors, as well as their role in the transition from compensated to decompensated hypertrophy utilizing unique gain- and loss-of-PKCalpha function transgenic mouse models that we have determined exhibit the anticipated loss-, and gain-of betaAR signaling phenotypes, respectively. In addition, we will assess whether selective inhibition of PKCalpha can attenuate the development of both hypertrophy and betaAR insensitivity in chronic pressure overload. Thus, we propose the following specific aims: 1) Determine the effects of PKCalpha activity on cardiac beta adrenergic receptor phosphorylation and heterologous desensitization; 2) Determine the role of PKCalpha activity in the transition from compensated to decompensated cardiac hypertrophy; and 3) Determine the effects of PKCalpha translocation on the cardiac response to ischemia-reperfusion injury. Accomplishment of these aims will demonstrate that PKCalpha is a potentially important therapeutic target in ischemic heart disease and heart failure.